Sclerostin Antibody-Induced Changes in Bone Mass Are Site Specific in Developing Crania

Abstract

Sclerostin antibody (Scl-Ab) is an anabolic bone agent that has been shown to increase bone mass in clinical trials of adult diseases of low bone mass, such as osteoporosis and osteogenesis imperfecta (OI). Its use to decrease bone fragility in pediatric OI has shown efficacy in several growing mouse models, suggesting translational potential to pediatric disorders of low bone mass. However, the effects of pharmacologic inhibition of sclerostin during periods of rapid growth and development have not yet been described with respect to the cranium, where lifelong deficiency of functioning sclerostin leads to patterns of excessive bone growth, cranial compression, and facial palsy. In the present study, we undertook dimensional and volumetric measurements in the skulls of growing Brtl/+ OI mice treated with Scl-Ab to examine whether therapy-induced phenotypic changes were similar to those observed clinically in patients with sclerosteosis or Van Buchem disorder. Mice treated between 3 and 14 weeks of age with high doses of Scl-Ab show significant calvarial thickening capable of rescuing OI-induced deficiencies in skull thickness. Other changes in cranial morphology, such as lengths and distances between anatomic landmarks, intracranial volume, and suture interdigitation, showed minimal effects of Scl-Ab when compared with growth-induced differences over the treatment duration. Treatment-induced narrowing of foramina was limited to sites of vascular but not neural passage, suggesting patterns of local regulation. Together, these findings reveal a site specificity of Scl-Ab action in the calvaria with no measurable cranial nerve impingement or brainstem compression. This differentiation from the observed outcomes of lifelong sclerostin deficiency complements reports of Scl-Ab treatment efficacy at other skeletal sites with the prospect of minimal cranial secondary complications. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Keywords: ANABOLIC EFFECT; CRANIAL MORPHOLOGY; OSTEOGENESIS IMPERFECTA; SCLEROSTIN ANTIBODY; VASCULARITY.

Figure 1:

A) Landmark locations and calculated values. B) Landmark locations measured on exertior of crania. C) Sample region of interest obtained for intracranial volume. D) Sample Foramen Magnum outline.

Figure 2:

A) Dorsal and lateral views of deformations for three pairwise group differences. Landmark locations are identified in reference view. 1. PIT; 2. IP/OP; 3. Lambda; 4. Bregma; 5. Nasion; 6. Nasale. B) Trajectory analysis demonstrates a statistically insignificant difference between veh WT (red), veh HET (green), and treated HET (blue) mean shapes. Lightly colored points represent individual measurements; darker points are means of each group. Dashed curves represent radii of statistical difference between groups.

Figure 3.

Micro-CT data from cranial landmark measurements demonstrate genotype and Scl-Ab effect on cranial lengths (A –E ) and (F –J ) on cranial angles. Superimposed mean lengths and angles of crania for (K ) Brtl/+ and (L ) WT mice. Data are shown as mean ± SEM of measurements.

Figure 4:

A) MicroCT data of the parietal bone reveals average parietal thickness is impacted by genotype and treatment. B) Sample parietal thickness regions of interest. Color look-up scale represents the measured thickness at each location in mm using local thickness computation. C, D) MicroCT imaging reveals intracranial volume is impacted by genotype, but not SclAb treatment. E) MicroCT data of the parietal suture reveals interdigitation is impacted by phenotype, but not Scl-Ab treatment. F) Sample suture outlines demonstrate interdigitation differs between genotype, but is not impacted by Scl-Ab. Data is shown as mean ± SEM of measurements.

Figure 5.

Micro-CT average cross-sectional measurements of foramen reveal the interpterygoid is the only foramen impacted by Scl-Ab (A –F ), despite genotypic differences (G ). Micro-CT of basivertebral foramen reveal Scl-Ab induces changes in average cross-sectional area. Data are shown as mean ± SEM of measurements.

Figure 6:

MicroCT average cross-sectional measurements of the anterior semicircular canal reveals A) Scl-Ab causing an increase in cross-section, with no impact by phenotype. B) Sample region of interest measured. Data is shown as mean ± SEM of measurements